1. Field of the Invention (Technical Field)
This invention relates to applications and methods for plasma treatment of coatings for enhanced biocompatible properties for implanted medical devices, including decreased restenosis and decreased adhesion of cells, such as platelets and leukocytes. The invention further relates to coated medical devices and methods, which include plasma-deposited nitrogen-containing and oxygen-containing coatings, and one or more additional coatings, including siloxane-containing coatings, polyethylene glycol-containing coatings and dextran-containing coatings.
2. Background Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
There is a need for coatings and surfaces of medical devices that limit or inhibit restenosis and attachment of cells, particularly attachment of platelets, leukocytes and similar cells. Medical devices, particularly implantable medical devices, frequently result in platelet attachment leading to thrombosis, leukocyte attachment leading to inflammation, and aberrant cellular in-growth leading to fibrosis and related conditions. For example, restenosis is a common problem following stent placement, involving overpopulation by smooth muscle cells with consequent re-narrowing of the lumen of the blood vessel. With stents and other blood-contacting medical devices, including catheters and similar devices, attachment of platelets and leukocytes is a significant problem. Substantial effort has been devoted to finding materials, coatings, surfactants, drugs and other substances that will inhibit either restenosis or attachment of cells.
Implantable medical devices are used for a wide variety of purposes. Thus devices such as stents, shunts, catheters, prosthetic heart valves, pacemakers, pulse generators, cardiac defibrillators, and similar devices and components are used in the treatment of cardiac and other diseases. A variety of screws, anchors, plates, joints and similar devices are used in orthopedic surgery. Catheters, drains, shunts, leads, stimulators, sensors, seeds, inducers and other devices are used in a wide variety of applications. These implantable medical devices are made from a wide variety of materials, including metals, plastics and various polymeric materials.
A large number of coatings have been explored for used with implantable medical devices to improve the biocompatibility or otherwise improve the in vivo behavior of the implant. U.S. Pat. No. 5,338,770 describes methods and materials for coating biomedical devices and implants with poly (ethylene oxide) chains suitable for covalent attachment of bioactive molecules intended to counteract blood-material incompatibility. U.S. Pat. No. 5,463,010 describes membranes, including polymerized aliphatic hydrocyclosiloxane monomers, for use in coating biomedical devices and implants, and suitable for use as a substrate for covalent attachment of other molecules. U.S. Pat. No. 5,824,049 describes multiple-layer coatings, providing for controlled release of a drug or other bioactive materials through a porous layer. U.S. Pat. No. 6,017,577 describes a polyurethane hydrogel coating for use in medical devices. These and a number of other references known in the art provide for some form of coating, and optionally a specific bioactive layer or coating, for use in improving biocompatibility. However, none of these methods or compositions has addressed all of the problems encountered with implantable medical devices, such as restenosis with stents and attachment of platelets and leukocytes, and none have resulted in widespread commercial and industrial acceptance.
There has been interest in use of a variety of substances in medical device coatings to decrease restenosis, cellular attachment or provide other biomedical benefits. For example, U.S. Pat. No. 6,087,479 discloses coatings, such as a nylon or plastic matrix coating, for use with nitric oxide adducts, such as sodium nitroprusside, and U.S. Pat. No. 5,665,077 discloses polymeric coatings with nitroso compounds. A number of articles in the scientific literature disclose related methods, for example, see Mowery K A et al: Preparation and characterization of hydrophobic polymeric films that are thromboresistant via nitric oxide release. Biomaterials 2000; 21:9-21; and Sly M K et al: Inhibition of surface-induced platelet activation by nitric oxide. ASAIO J 1995 41:M394-8.
A recognized problem with stents, and particularly coated stents, is that the coating itself induces an inflammatory response or a thrombogenic response, either of which can lead to unwanted biological consequences. Furthermore, both inflammatory responses and thrombogenic responses appear to be implicated in restenosis in that these responses elicit local production or secretion of growth factors, leading to restenosis. A large number of agents have been investigated, used both systemically and locally, to overcome these responses. Tranilast is one such agent, and is a small molecule with a number of biological actions. It is used in Japan as an anti-allergy drug and acts as an anti-inflammatory on mast cells. It also inhibits arterial smooth muscle cell proliferation and migration in vitro and restenosis in vivo. It is currently under evaluation in clinical trials as a systemic agent to limit restenosis following balloon angioplasty. Pactitaxel (taxol) has also been described as having a beneficial effect following local administration, including when used in a stent coating (Herdeg et al. Semin Interv Cardiol 1999, 3:197-9; Baumbach et al., Catheter Cardiovasc Interv 1999, 47:1026). Also, local administration of a glycoprotein IIb/IIIa receptor antagonist or anti-thrombin agent stents reportedly reduced platelet deposition in coronary arteries (Santos et al. Am J Cardiol 1998, 82:673-5, A8; Kruse Catheter Cardiovasc Interv 1999, 46:503-7). Intramural delivery of a specific tyrosine kinase inhibitor with a biodegradable stent reportedly suppressed restenotic changes of the coronary artery in pigs in vivo (Yamawaki et al J Am Coll Cardiol 1998, 32:780-6). Also, dexamethazone has been delivered locally with stents (Lincoff et al. J Am Coll Cardiol 1997, 29:808-16; Strecker Cardiovasc Intervent Radiol 1998, 21(6): 487-96).
Plasma processes have been used in manufacture of medical devices, primarily for use in surface cleaning and preparation methods (Aronsson et al., J Biomed Mat Res 1997, 35:49-73). However, plasma processes have also been used to introduce groups, such as amine groups, into a surface, as described in U.S. Pat. No. 5,338,770. That patent describes a method of introduction of amine groups using ammonia gas in the plasma chamber at a flow rate of 190 micromoles per second at 170 mTorr absolute pressure, with the target, hollow fibers, exposed to 180 watts at a radio frequency of 13.56 MHz for fifteen minutes. Plasma processes have also been used to introduce various coatings and polymeric groups, as described generally in U.S. Pat. Nos. 5,463,010 (hydrocyclosiloxane membrane), 5,336,518 (heptafluorobutylmethacrylate membrane), 5,962,138 (plasma film layers of various monomers), and other references. However, none of these processes have demonstrated both decreased restenosis and decreased attachment of cells such as platelets and leukocytes when used in vivo.
Thus it would be desirable to provide coatings for surfaces of medical devices which exhibit decreased restenosis and decreased attachment of cells. In particular, it would be desirable to provide methods for preparing and fabricating devices and substrates for treating or preventing hyperplasia, inflammation, thrombosis, and other disease conditions. The methods should be useful with both permanently implanted devices, such as vascular stents, grafts, and coils, as well as temporarily implanted devices, such as catheters, wires, pellets, and the like. The fabrication methods should be convenient, economical, and efficacious.
However, notwithstanding the work that has been done, a simple and reliable method of causing stents, catheters and other medical devices to inhibit cellular attachment, and in the case of stents and other devices within a blood vessel, to inhibit restenosis, has still not been demonstrated. This invention addresses that specific need.
The invention provides an implantable medical device with a plasma-modified surface, which medical device has at least one contacting surface for contacting a bodily fluid or tissue, wherein the contacting surface is modified by plasma treatment in a plasma including nitrogen-containing molecules and oxygen-containing molecules. In one embodiment, the nitrogen-containing molecules each comprise no more than six atoms, and preferably four or fewer atoms. The nitrogen-containing molecules may include NH3, NH4, N2O, NO, NO2 and N2O4. The oxygen-containing molecules may include O2 and O3. The plasma treatment with the nitrogen-containing molecules and the oxygen-containing molecules may be simultaneous. In the device, the plasma-modified contacting surface exhibits decreased adhesion of at least some mammalian cells, compared to a similar contacting surface that is not plasma-modified. The mammalian cells may be platelets or leukocytes.
The medical device may be a stent wherein the at least one contacting surface includes at least the lumen of the stent. The plasma-modified contacting surface comprising the lumen of the stent exhibits decreased restenosis subsequent to placement in a blood vessel, compared to a similar stent that is not plasma-modified.
The plasma treatment is for less than about five minutes, preferably for less than about two minutes, more preferably for less than about one minute, and most preferably for between about thirty seconds and about one minute.
In one embodiment, the plasma treatment is of a plasma wherein the nitrogen-containing molecules are NH3 and the oxygen-containing molecules are O2. The mass flow rate during plasma treatment with each of NH3 and of O2 is between a ratio of about 1.5:1 and about 1:1.5. In an alternative embodiment, the plasma treatment is of a plasma wherein the nitrogen-containing molecules are N2O and the oxygen-containing molecules are O2. The mass flow rate during plasma treatment with each of N2O and of O2 is between a ratio of about 1.5:1 and about 1:1.5.
The medical devices of this invention include stents, catheters, balloons, shunts, valves, pacemakers, pulse generators, cardiac defibrillators, spinal stimulators, brain stimulators, sacral nerve stimulators, leads, inducers, sensors, seeds, screws, anchors, plates and joints. The at least one contacting surface may be a metallic material, or may be a polymeric material. If it is a polymeric material, it may be biodegradable.
The device can further include a biologically compatible coating deposited over the plasma including nitrogen-containing molecules and oxygen-containing molecules. In one embodiment, the biologically compatible coating is a membrane formed from the plasma polymerization of hydrocyclosiloxane monomer of the general formula: 
wherein R is an aliphatic group having 1 to about 5 carbon atoms and n is an integer from 2 to about 10. This hydrocyclosiloxane monomer may be 1,3,5,7-tetramethylhydrocyclotetrasiloxane, 1,3,5,7, 9-pentamethylhydrocyclopentasiloxane, 1,3,5,7,9,11-hexamethylhydrocyclohexasiloxane, or a mixture of 1,3,5,7,9-pentamethylcyclopentasiloxane and 1,3,5,7,9,11-hexamethylcyclohexasiloxane monomers.
In an alternative embodiment, the biologically compatible coating may be a polymer or co-polymer, such as poly acrylate, poly bisphenol A carbonate, polybutadiene, polycarbonate, poly butylene terephthalate, poly butryl methacrylate, polydimethyl siloxane, polyester, polyethyleneimine, poly methyl methacrylate, polypropylene, polystyrene, polysulfone, polyurethane, poly vinyl, poly vinyl acetate polylactide, polyglycolide, polycaprolactone, or polyvinylidine fluoride.
The invention further consists of a coating for an implantable medical device with at least one contacting surface for contacting a bodily fluid or tissue, which coating includes a first layer on the contacting surface that include the product of plasma treatment with a plasma comprising nitrogen-containing molecules and oxygen-containing molecules. The coating may further include a second layer posited over the first layer, which second layer includes the product of plasma polymerization of hydrocyclosiloxane monomer of the general formula: 
wherein R is an aliphatic group having 1 to about 5 carbon atoms and n is an integer from 2 to about 10. The coating may further include a third layer posited over the second layer, which third layer includes the product of plasma polymerization of monomers such as fluorocarbon monomers, organo-based monomers such as ethylene, allylamine, N-trimethylsilyl-allylamine, hydrocarbons, N-protected unsaturated amines, N-unprotected unsaturated amines, N-protected cyclic aliphatic amines, N-unprotected cyclic aliphatic amines, mercaptans, nitriles and organophosphorus compounds; and functionalizing monomers such as N2, CO2, NH3 and SO2. This coating may also include a polyoxyalkylene tether of the formula: 
wherein R1 is selected from an N-benzotriazole group, an N-2-pyrrolidinone group, or an 2-oxypyrimidine group; R2, R3 and R4 are independently selected alkylene groups of about 2 to about 3 carbon atoms and may be the same or different; R5 is selected from hydrogen, methyl, a carbonyloxy-N-benzotriazole group, a carbonyloxy-N-2-pyrrolidinone group, and a carbonyl-2-oxypyrimidine group; a is an integer from 1 to 1000 and each of b and c is an integer from 0 to 1000, where a+b+c is an integer from 3 to 1000, under conditions whereby the R5 group reacts with a free amino group of the third layer thereby forming a covalent bond to give a modified polymeric surface having activated polyoxyalkylene groups covalently bonded thereto. One or bioactive compounds, including an aminoglycan polysaccharide, an amino polysaccharide, a peptide, a polypeptide, a protein, a compound having antithrombotic or thrombolytic properties, a compound having anti-inflammatory properties, a compound having cytostatic properties, a compound having cytotoxic properties, or a metal chelator, may be covalently bonded to the activated polyoxyalkylene groups of the polyoxyalkylene tether.
In one embodiment of the coating, the nitrogen-containing molecules each comprise no more than six atoms, and preferably four or fewer atoms. The nitrogen-containing molecules may include NH3, (NH4)+, N2O, NO, NO2 and N2O4. The oxygen-containing molecules may include O2 and O3. The plasma treatment with the nitrogen-containing molecules and the oxygen-containing molecules may be simultaneous. The plasma treatment for the coating is for less than about five minutes, preferably for less than about two minutes, more preferably for less than about one minute, and most preferably for between about thirty seconds and about one minute.
In one embodiment, the plasma treatment is of a plasma wherein the nitrogen-containing molecules are NH3 and the oxygen-containing molecules are O2. The mass flow rate during plasma treatment of each of NH3 and of O2 is between a ratio of about 1.5:1 and about 1:1.5. In an alternative embodiment, the plasma treatment is with a plasma wherein the nitrogen-containing molecules are N2O and the oxygen-containing molecules are O2. The mass flow rate during plasma treatment of each of N2O and of O2 is between a ratio of about 1.5:1 and about 1:1.5.
The hydrocyclosiloxane monomer of the second layer of the coating may be 1,3,5, 7-tetramethylhydrocyclotetrasiloxane, 1,3,5,7,9-pentamethylhydrocyclopentasiloxane, 1,3,5,7, 9,11-hexamethylhydrocyclohexasiloxane, or a mixture of 1,3,5,7,9-pentamethylcyclopentasiloxane and 1,3,5,7,9,11-hexamethylcyclohexasiloxane monomers.
In an alternative embodiment, the second layer of the coating may be a polymer or co-polymer such as poly acrylate, poly bisphenol A carbonate, polybutadiene, polycarbonate, poly butylene terephthalate, poly butryl methacrylate, polydimethyl siloxane, polyester, polyethyleneimine, poly methyl methacrylate, polypropylene, polystyrene, polysulfone, polyurethane, poly vinyl, poly vinyl acetate, polylactide, polyglycolide, polycaprolactone or polyvinylidine fluoride.
In the embodiment in which a polyoxyalkylene tether is applied to the third layer, it may be a polyethylene glycol. In one embodiment, the polyoxyalkylene tether is poly(oxythylene)-(N-hydroxybenzotriazolyl). The bioactive compound may be amino dextran or another complex polysaccharide or amino glycan.
The invention further includes implantable medical devices with at least one contacting surface for contacting a bodily fluid or tissue, wherein the contacting surface comprises a coating of any one of the first layer, the first layer and any one of the second layers, or the first layer, any one of the second layers, and any one of the third layers. Such devices may be stents, catheters, balloons, shunts, valves, pacemakers, pulse generators, cardiac defibrillators, spinal stimulators, brain stimulators, sacral nerve stimulators, leads, inducers, sensors, seeds, anti-adhesion sheets, screws, anchors, plates or joints, among other exemplary medical devices. The at least one contacting surface may be a metallic material or a polymeric material.
The invention further provides a method of imparting bioactive properties to a surface by modifying the surface by plasma treatment with a plasma comprising nitrogen-containing molecules and oxygen-containing molecules. In one embodiment of the method, the nitrogen-containing molecules each comprise no more than six atoms, and preferably four or fewer atoms. The nitrogen-containing molecules may include NH3, (NH4)+, N2O, NO, NO2 and N2O4. The oxygen-containing molecules may include O2 and O3. The plasma treatment with the nitrogen-containing molecules and the oxygen-containing molecules may be simultaneous. In the method, the plasma-modified contacting surface exhibits decreased adhesion of at least some mammalian cells, compared to a similar contacting surface that is not plasma-modified. The mammalian cells may be platelets or leukocytes. The plasma treatment is for less than about five minutes, preferably for less than about two minutes, more preferably for less than about one minute, and most preferably for between about thirty seconds and about one minute.
In one embodiment of the method, the plasma treatment is with a plasma wherein the nitrogen-containing molecules are NH3 and the oxygen-containing molecules are O2. The mass flow rate during plasma treatment with each of NH3 and of O2 is between a ratio of about 1.5:1 and about 1:1.5. In an alternative embodiment, the plasma treatment is with a plasma wherein the nitrogen-containing molecules are N2O and the oxygen-containing molecules are O2. The mass flow rate during plasma treatment with each of N2O and of O2 is between a ratio of about 1.5:1 and about 1:1.5.
The method can also include the step of applying a biologically compatible coating subsequent to modifying the surface by plasma treatment. The biologically compatible coating is made by plasma polymerization of hydrocyclosiloxane monomer of the general formula: 
where R is an aliphatic group having 1 to about 5 carbon atoms and n is an integer from 2 to about 10. The hydrocyclosiloxane monomer may be 1,3,5,7-tetramethylhydrocyclotetrasiloxane, 1,3,5,7, 9-pentamethylhyd rocyclopentasiloxane, 1,3,5,7,9,11-hexamethylhydrocyclohexasiloxane, or a mixture of 1,3,5,7,9-pentamethylcyclopentasiloxane and 1,3,5,7,9,11-hexamethylcyclohexasiloxane monomers.
In an alternative embodiment of the method, the biologically compatible coating may be a polymer or co-polymer such as poly acrylate, poly bisphenol A carbonate, polybutadiene, polycarbonate, poly butylene terephthalate, poly butryl methacrylate, polydimethyl siloxane, polyester, polyethyleneimine, poly methyl methacrylate, polypropylene, polystyrene, polysulfone, polyurethane, poly vinyl, poly vinyl acetate, polyglycolide, polylactide, polycaprolactone, or polyvinyledine fluoride.
If the biologically compatible coating is made by plasma polymerization of hydrocyclosiloxane monomer, the method may further include plasma polymerization of monomers such as fluorocarbon monomers, organo-based monomers such as ethylene, allylamine, N-trimethylsilyl-allylamine, hydrocarbons, N-protected unsaturated amines, N-unprotected unsaturated amines, N-protected cyclic aliphatic amines, N-unprotected cyclic aliphatic amines, mercaptans, nitriles and organophosphorus compounds; and functionalizing monomers such as N2, CO2, NH3 and SO2.
The coating may also include covalently bonding a polyoxyalkylene tether of the formula: 
wherein R1 is selected from an N-benzotriazole group, an N-2-pyrrolidinone group, or an 2-oxypyrimidine group; R2, R3 and R4 are independently selected alkylene groups of about 2 to about 3 carbon atoms and may be the same or different; R5 is selected from hydrogen, methyl, a carbonyloxy-N-benzotriazole group, a carbonyloxy-N-2-pyrrolidinone group, and a carbonyl-2-oxypyrimidine group; a is an integer from 1 to 1000 and each of b and c is an integer from 0 to 1000, where a+b+c is an integer from 3 to 1000, under conditions whereby the R5 group reacts with a free amino group of a monomer, thereby forming a covalent bond to give a modified polymeric surface having activated polyoxyalkylene groups covalently bonded thereto. A bioactive compound may then be covalently bonded to the activated polyoxyalkylene groups of the polyoxyalkylene tether, using such bioactive compounds as aminoglycan polysaccharide, amino polysaccharide, peptides, polypeptides, proteins, compounds having antithrombotic or thrombolytic properties, compounds having anti-inflammatory properties, compounds having cytostatic properties, a compound having cytotoxic properties, and metal chelators.
A primary object of the present invention is to provide a plasma-deposited surface including a nitrogen-containing molecular species and an oxygen-containing molecular species wherein the resulting surface exhibits decreased cellular adhesion or increased cellular apoptosis.
Another object of the present invention is to provide modified surface of a medical device that includes one or more species of nitrogen-containing elements wherein the surface exhibits decreased cellular adhesion or increased cellular apoptosis.
Another object of the present invention is to provide a plasma-deposited surface including a nitrogen-containing molecular species and an oxygen-containing molecular species wherein the resulting surface, when applied to a stent or other vascular device, exhibits decreased restenosis concomitant with decreased cellular adhesion or increased cellular apoptosis.
Another object of the present invention is to provide modified surface of a vascular medical device, such as a stent, that includes one or more species of nitrogen-containing elements wherein the surface exhibits decreased restenosis and decreased cellular adhesion or increased cellular apoptosis.
Another object of the present invention is to provide a method for modifying, by plasma glow discharge, a surface of a medical device by means of simultaneous plasma treatment with NH3 and O2.
Another object of the present invention is to provide a method for modifying, by plasma glow discharge, a surface of a medical device by means of simultaneous plasma treatment with N2O and O2.
Another object of the present invention is to provide a method for modifying, by plasma glow discharge, a surface of a medical device by means of simultaneous plasma treatment with a nitrogen-containing molecular species and an oxygen-containing molecular species for a period of less than five minutes, preferably less than one minute, and most preferably between about thirty seconds and one minute.
Another object of the present invention is to provide a method for modifying, by plasma glow discharge, a surface of a medical device by means of simultaneous plasma treatment with approximately equal quantities, by mass flow rates, of a nitrogen-containing molecular species and an oxygen-containing molecular species.
Other objects, advantages and novel features, and further scope of applicability of the present invention will be set forth in part in the detailed description to follow, taken in conjunction with the accompanying drawings, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.